Note: Descriptions are shown in the official language in which they were submitted.
CA 02305258 2000-04-07
1
SUBSTITUTED TETRAHYDROPYRIDOPYRIMIDINONE DERIVATIVES
METHOD FOR PRODUCING THE SAME AND THEIR USE
The invention relates to 3-substituted tetrahydropyrido-
pyrimidinone derivatives, their preparation and use for producing
active ingredients for drugs.
classical antidepressants and the newer selective serotonin
reuptake inhibitors (SSRIs) develop their antidepressant effect
inter alia by inhibiting active reuptake of the transmitter into
the presynaptic nerve endings. Unfortunately, the antidepressant
effect thereof does not have its onset until treatment has lasted
at least 3 weeks, and, moreover, about 30% of patients are
therapy-resistant.
Blockade of presynaptic serotonin autoreceptors increases, by
abolishing negative coupling, the serotonin release and thus the
current transmitter concentration in the synaptic cleft. This
increase in the transmitter concentra~ion is regarded as the
principle of the antidepressant effect. This mechanism of action
differs from previously known antidepressants which activate both
the presynaptic and somatodendritic autoreceptors and therefore
result in a delayed onset of action, only after desensitization
of these autoreceptors. Direct autoreceptor blockade bypasses
this effect.
The derivatives described in JP 08027149 and JP 04054181 are
known.
According to current knowledge, the presynaptic serotonin
autoreceptor is of the 5-HT1B subtype (Fink et al., Arch.
Pharmacol. 352 (1995), 451). Selective blockade thereof by
5-HT1B~D antagonists increases the serotonin release in the brain:
G.W. Price et al., Behavioural Brain Research 73 (1996), 79-82;
P.H. Hutson et al., Neuropharmacology Vol. 34, No. 4 (1995),
383-392.
However, surprisingly, the selective 5-HT1B antagonist GR 127 935
reduces serotonin release in the cortex after systemic
administration. One explanation might be stimulation of
somatodendritic 5-HT1A receptors in the raphe region by the
released serotonin, which inhibits the firing rate of
0050/48479 ca o23o525s 2000-04-0~
2
serotonergic neurons and thus serotonin release (M. Skingle et
al., Neuropharmacology Vol. 34 No. 4 (1995), 377-382, 393-402).
One strategy for bypassing the autoinhibitory effects in
serotonergic areas of origin thus aims at blockade of presynaptic
5-HT1B receptors. This hypothesis is supported by the observation
that the effect of paroxetine on serotonin release in the dorsal
raphe nucleus of the rat is potentiated by the 5-HT1B receptor
antagonist GR 127 935 (Davidson and Stamford, Neuroscience
Letts., 188 (1995), 41).
The second strategy includes blockade of both types of
autoreceptors, namely the 5-HT1A receptors, in order to intensify
neuronal firing, and the 5-HT1$ receptors, in order to increase
terminal serotonin release (Starkey and Skingle,
Neuropharmacology 33 (3-4) (1994), 393).
5-HT1B~D antagonists, alone or coupled to a 5-HT1A receptor
antagonistic component, should therefore cause a greater increase
in serotonin release in the brain and'~might therefore be
associated with advantages in the therapy of depressions and
related psychological disorders.
It has now been found that 3-substituted tetrahydropyrido-
pyrimidinone derivatives of the formula I
O
X\~N- A- B- Ar
Y J (I).
N
where
one of the two radicals X and Y is C.H2 and the other is NR1,
R1 is hydrogen, (C1_6) alkyl branched or unbranched,
CO-(C1_4)-alkyl, COztBu, CO-aryl and a phenylalkyl-C1-C4
radical which in turn may be substituted on the aromatic
system by F, C1, Br, I, C1-C4 alkyl, C1-C4 alkoxy,
trifluoromethyl, hydroxyl, amino, cyano or nitro,
0050/48479 ca o23os2ss 2000-04-0~
3
A is branched or unbranched (Cl_~o)-alkylene or straight-chain or
branched (C2_lo)-alkylene which comprises at least one group Z
which is selected from O, S, NR2, cyclopropyl, CHOH, a double
or triple bond,
R2 is hydrogen and C1-C4 alkyl,
B is 4-piperidine, 4-tetrahydro-1,2,3,6 pyridine, 4-piperazine
or the corresponding cyclic compounds enlarged by one
methylene group, with the linkage to A being via an N atom of
B, and
Ar is phenyl which is unsubstituted or substituted by (C1_6)
alkyl branched or unbranched, O-(C1_6) alkyl branched or
unbranched, OH, F, C1, Br, I, trifluoromethyl, NRzz, COzRz,
cyano or phenyl, or is tetralin, indan, fused aromatic
systems such as naphthalene which is unsubstituted or
substituted by ( C1_4 ) -alkyl or O ( C1_4 ) -alkyl , anthracene or 5-
or 6-membered aromatic heterocycles having 1 or 2 heteroatoms
which are selected, independently of one another, from O and
N, which may be fused to other aromatic radicals,
and their salts with physiologically tolerated acids, have
valuable pharmacological properties.
Particularly preferred compounds are those where
°ne of the two radicals X and Y is CH2 and the other is NR1,
R1 is hydrogen, (C1_4)-alkyl branched or unbranched, CO-(C1_4)-
alkyl, C02tBu, COPh or a phenylalkyl C1-CZ radical which in
turn can be substituted on the aromatic system by F, C1, Br,
I~ Ci-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, hydroxyl or
cyano,
A is (Cz_5) alkylene branched or unbranched or (CZ_5)-alkylene
which comprises a group Z which is selected from CHOH,
cyclopropyl, a double or a triple bond,
B is 4-piperidine, 4-tetrahydro-1,2,3,6 pyridine, 4-piperazine
or homopiperazine, where the linkage to A takes place via an
N atom of B, and
0050/48479 ca o23o525s 2000-04-0~
4
Ar is phenyl which is unsubstituted or substituted by (C1_6)-
alkyl branched or unbranched, O-(C1_6)-alkyl branched or
unbranched, F, C1, Br, I, trifluoromethyl, COzR2, NRZZ, cyano
or phenyl, or is tetralin, indan, fused aromatic systems such
as naphthalene which is unsubstituted or substituted by (C1_4)
alkyl or O(C1_4) alkyl, or 5- or 6-membered aromatic
heterocycles having 1 or 2 nitrogen atoms, which may be fused
to other aromatic radicals.
particularly preferred compounds of. the formula I are those
listed in claim 3.
The compounds of the formula I may have one or more centers of
asymmetry. The invention therefore includes not only the
racemates but also the relevant enantiomers and diastereomers.
The invention also includes the respective tautomeric forms.
The novel compounds of the formula I can be prepared by reacting
a compound of the formula II
O
X I ~ N- A- Q
(II),
Y
N
where A, X and Y have the abovementioned meanings, and Q is a
group which can be eliminated (eg. C1, Br, I, alkanesulfonyloxy
or arylsulfonyloxy), with a compound of the formula III,
H-B-Ar (III),
where B and Ar have the abovementioned meanings, in a manner
known per se, and converting the compound obtained in this way
where appropriate into the addition salt with a physiologically
tolerated acid. It is likewise possible to react a compound of
the formula IV
0
X~ J H (IV)
N
with a compound of the formula V
0050/48479 CA 02305258 2000-04-07
Q-A-B-Ar (V)
in a manner known per se.
5
Another variant of the synthesis comprises linking a compound of
the formula VI
O
X I ~ N- A- CHO
(VI)
N
with a compound of the formula III by a reductive amination known
per se.
Compounds of the formula III can be synthesized by
1' Linking compounds of the formula VII
W-B1 (VII)
where B1 is piperazine or homopiperazine and W is hydrogen or
one of the usual amino protective groups (eg. Boc or Cbz),
with a compound of the formula VIII
P-Ar (VIII),
where P is B(OH)z, SnR3, OTf, Br, Cl, or I, and R is
C1-C4-alkyl, in a known manner; or
2. linking compounds of the formula.. IX
W-B2-P1 (IX),
where Bz is 4-tetrahydro-1,2,3,6-pyridine and the
corresponding cyclic compounds enlarged by one methylene
group, and P1 is C1, Br, I, SnR,, where R is C1-C4-alkyl, or
OTf, with a compound of the formula X
0050/48479 ca o23o525s 2000-04-07
6
P-Ar (X),
where W, P and Ar each have the abovementioned meanings, and
the reactions take place by known processes as described, for
example, in
S.L. Buchwald et al. J. Am. Chem. Soc. 1996, 118, 7215,
J.F. Hartwig et al. Tetrahedron Lett. 1995, 36, 3604 ,
J~K. Stille et al. Angew. Chem: 1986, 98, 504, .
S.L. Buchwald et al. Angew. Chem. 1995, 107, 1456 or
J.F. Hartwig et al. J. Am. Chem. Soc 1996, 1I8, 7217 or
J.F. Hartwig et al. J. Org. Chem. 1997, 62, 1268,
S.L. Buchwald et al. J. Org. Chem. 1997, 62, 1264 and the
literature cited therein or
S.L. Buchwald et al J. Am. Chem. Soc 1997, 119, 6054,
J.K. Stille, Angew. Chem. 1986, 98, 504 or
J.K.Stille et al. J.Org. Chem. 1990, 55, 3014,
M. Pereyre et al. "Tin in Organic Synthesis", Butterworth
1987; or
3~ reducing compounds of the formula (XI)
W-B2-Ar (XI),
where B2 has the abovementioned meaning, to compounds of the
formula XII
W-B3-Ar ( XII ) ,
where B3 is piperidines linked in the 1,4 positions, and the
corresponding ring compounds enlarged by one methylene group;
or
4. cyclizing compounds of the formula XIII
W-N- ( CzH,Q ) Z ( XI I I ) ,
0050/48479 ca o23o525s 2000-04-0~
7
where W and Q have the meanings.described above, with a
compound of the formula XIV
NH2-Ar ( XIV ) ,
where Ar has the abovementioned meaning, to give compounds of
the formula XV
W-B1-Ar ( XV ) .
The substances of the formulae III and V which are required as
starting materials for synthesizing the novel compounds are known
or can be synthesized by known processes (eg. Organikum Barth Dt.
Verl. der Wiss. 1993 or A. R. Katritzky, C. W. Rees (ed.)
Comprehensive Heterocyclic Chemistry Pergamon Press) from
analogous precursors.
Further reaction of the compounds
H-B-Ar (III)
prepared as in 1. to 4., with subsequent elimination of any
protective groups, to give compounds of the formula V takes place
by linkage with compounds of the formula XVI
Q-A-Q' (XVI),
where Q and Q' are leaving groups, under conditions known per se.
The substances of the formula II, IV, VI and of the formula P-Ar,
NHz-Ar, W-B1 and W-BZ-P1 required as starting materials for
synthesizing the novel compounds are known or can be synthesized
from similar precursors by methods described in the literature
(eg. B. Dumaitre, N. Dodic J. Med. Chem. 1996, 39, 1635 or
A. Yokoo et al. Bull. Chem. Soc. Jpn. 1956, 29, 631 or
L. Borjeson et al. Acta Chem. Chem. [sic] 1991, 45, 621 or
Organikum Barth Dt. Verl. der Wiss. 1993 or A. R. Katritzky, C.
W. Rees (ed.) Comprehensive Heterocyclic Chemistry Pergamon Press
0050/48479 ca o23o525s 2000-04-0~
8
or The Chemistry of Neterocyclic Compounds J. Wiley & Sons Inc.
NY and the literature cited in each of these).
The reactions described above generally take place in an inert
organic solvent, eg. dimethylformamide, acetonitrile,
dichloromethane, dimethyl sulfoxide, dimethoxyethane, toluene,
ethyl acetate, xylene, a ketone such as acetone or methyl ethyl
ketone, an alcohol such as ethanol or n-butanol, or a cyclic
saturated ether, eg. tetrahydrofuran or dioxane.
The reactions generally take place at from 20°C to the boiling
point of the solvent and are generally complete within 1 to 20
hours. If required, they take place in the presence of an
acid-binding agent such as sodium or potassium carbonate, sodium
methoxide, sodium ethoxide, sodium hydride, organometallic
compounds (butyllithium, alkylmagnesium compounds), potassium
t-butoxide, pyridine or triethylamine.
Where appropriate, the reactions take place with use of a
catalyst such as transition metals and their complexes, eg. Pd-C,
Pd(PPh,)" Pd(OAc)2, Pd(P(oTol)3),, Pd2(dba)3 or Ni(COD)2.
The crude product is isolated in a conventional way, for example
by filtration, removal of the solvent by distillation or
extraction from the reaction mixture.
The novel compounds of the formula I can be purified either by
recrystallization from conventional organic solvent or by column
chromatography.
Besides the 3-substituted tetrahydropyridopyrimidinone
derivatives, the invention also comprises the acid addition salts
°f the compounds of the formula I with physiologically tolerated
acids. Examples of suitable physiologically tolerated organic and
inorganic acids are hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, oxalic acid, malefic acid, fumaric
acid, lactic acid, tartaric acid, adipic acid or benzoic acid.
Further acids which can be used are described in "Fortschritte
der Arzneimittelforschung", Volume 10, pages 224 et seq.,
Birkhauser Verlag, Basle and Stuttgart, 1966.
The acid addition salts are prepared in a conventional way by
mixing the free base with the appropriate acid, where appropriate
in solution in an organic solvent, eg. a lower alcohol such as
methanol, ethanol or propanol, an ether such as methyl t-butyl
0050/48479 ca o23o525s 2000-04-07
9
ether, a ketone such as acetone or methyl ethyl ketone, or an
ester such as ethyl acetate.
The invention accordingly also relates to a therapeutic
composition which comprises a compound of the formula I or its
pharmacologically suitable acid addition salt as active
ingredient in addition to conventional carriers and diluents, and
to the use of the novel compounds for controlling diseases.
The novel compounds can be administered orally or parenterally,
intravenously or intramuscularly, in a conventional way.
The dosage depends on the age, condition and weight of the
Patient and on the mode of administration. As a rule, the daily
dose of active ingredient is about 1-100 mg/kg of body weight on
oral administration and 0.1-10 mg/kg of body weight on parenteral
administration.
The novel compounds can be used in conventional solid or liquid
pharmaceutical forms, eg. as uncoated or (film)coated tablets,
capsules, powders, granules, suppositories, solutions, ointments,
creams or sprays. These are produced in a conventional way. The
active ingredients can for this purpose be processed with
conventional pharmaceutical auxiliaries such as tablet binders,
fillers, preservatives, tablet disintegrants, flow regulators,
plasticizers, wetting agents, dispersants, emulsifiers, solvents,
release-slowing agents, antioxidants and/or propellant gases (cf.
H. Sucker et. al: Pharmazeutische Technologie, Thieme-Verlag,
Stuttgart, 1978). The administration forms obtained in this way
normally contain from 1 to 99$ by weight of active ingredient.
The novel compounds have a high affinity for 5-HT1B, 5-HT1D and
5-HT1A serotonin receptors. Approximately the same degree of
affinity, at least of the same order of magnitude, is shown for
these receptors. In addition, some of the novel compounds show
_ good inhibition of serotonin reuptake, a principle which is
implemented in most antidepressants.
These compounds are suitable as drugs for treating pathological
states in which the serotonin concentration is reduced and in
which it is wished for therapeutic purposes to block specifically
the activity of the presynaptic 5-HT1B, 5-HT1A, 5-HT1D receptors
without having a great effect on other receptors. An example of
such a pathological state is depression.
0050/48479 ca o23os2ss 2000-04-07
The compounds of the present invention can also be of use for
treating mood disturbances with a central nervous causation, such
as seasonal affective disorders and dysthymia. These also include
anxiety states such as generalized anxiety, panic attacks,
5 sociophobia, obsessive-compulsive neuroses and post-traumatic
stress symptoms, memory disturbances including dementia, amnesias
and age-related loss of memory, and psychogenic eating disorders
such as anorexia nervosa and bulimia nervosa.
10 The novel compounds can additionally be used to treat endocrine
disorders such as hyperprolactinemia and to treat vasospasms
(especially of the cerebral vessels), hypertension and
gastrointestinal disorders associated with disturbances of
motility and secretion. Another area of use comprises sexual
disorders.
25
The following examples serve to illustrate the invention without
restricting it.
Example 1:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-3,5,7,8-tetra-
hydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine
Preparation of the starting materials
a) 3,5,7,8-Tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine
4.7 g of sodium were reacted in small portions with 250 ml of
ethanol and then, at 5-10°C, a suspension of 14.2 g
(0.05 mol) of methyl N-benzyl-4-piperidone-3-carboxylate in
ethanol was added dropwise. After stirring for 30 minutes,
6 g (0.075 mol) of formamidine hydrochloride were slowly
added and the reaction mixture was refluxed for 10 h. The
solvent was removed under reduced pressure, and the residue
was adjusted in 100 ml of water to pH = 6.5 - 7 with 2N
hydrochloric acid so that the product precipitated. The
crystals were filtered off with suction and dried in a vacuum
oven, and 8 g (66~) were isolated in this way. Melting point
88°C.
0050/48479 ca o23os2ss 2000-04-07
11
3,5,7,8-Tetrahydro-4-oxo-6-benzylpyrido[3,4-d]pyrimidine
(melting point 199°C) and 1,1-dimethyl [sic]
3,5,7,8-tetrahydro-4-oxopyrido[4,3-d]pyrimidine-6-carboxylate
(melting point 160°C) were obtained in a similar way.
b) 1-(2-methoxyphenyl)-4-(2-chloroeth-1-yl)piperazine
19.2 g (0.1 mol) of o-methoxyphenylpiperazine and 13.8 g
(0~1 mol) of potassium carbonate were dissolved in 200 ml of
DMF at room temperature and, after 30 min, 30 ml (0.36 mol)
of 1-bromo-2-chloroethane were added. The mixture was stirred
at room temperature for 2 h. Pouring into ice-water was
followed by extraction with methyl tert-butyl ether, and the
organic phases were washed with water, dried with sodium
sulfate and then concentrated. 30$ strength isopropanolic HC1
solution was added to the solution of the residue in ethyl
acetate to precipitate the hydrochloride, which was filtered
off with suction and dried in a vacuum drying oven at 40°C.
17 g (67~) of substance were obtained. Melting point 200°C.
1-(2-Methoxyphenyl)-4-(3-chloroprop-1-yl)piperazine (melting
point 217°C, hydrochloride), 1-(3,4-dimethylphenyl)-4-(2-
chloroeth-1-yl)piperazine (melting point 260°C,
hydrochloride), 1-(2-pyrimidyl)-4-(2-chloroeth-
1-yl)piperazine (melting point 270°C, hydrochloride),
1-(1-naphthyl)-4-(3-chloroprop-1-yl)- piperazine (melting
point 217°C, hydrochloride) were obtained in a similar way.
Two examples of syntheses of the piperazines are indicated below.
1-(5-Tetralinyl)piperazine
14,7 g (0.1 mol) of 5-aminotetralin and 18 g (0.11 mol) of
bis((3-chloroethyl)amine hydrochloride in 300 ml of n-butanol were
refluxed for 48 h and cooled, 5.4 g of sodium carbonate were
-. added and the mixture was refluxed for a further 20 h. The
precipitate which resulted on cooling was filtered off with
suction and taken up in water, and 2N sodium hydroxide solution
was added. The aqueous phase was extracted with ethyl acetate,
and washing with water was followed by drying over sodium sulfate
and concentration under reduced pressure. 10.7 g (50~) of the
product were isolated as an oil in this way.
4-(1-piperazinyl)isoquinoline
0050/48479 ca o23o525s 2000-04-0~
12
4.51 g (21.7 mmol) of 4-bromoisoquinoline, 4.65 g (25.0 mmol) of
t-butyl piperazine-N-carboxylate, 0.1 g (0.11 mmol) of
tris(dibenzylideneacetone) dipalladium, 0.11 g (0.18 mmol) of
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 2.92 g
(30.4 mmol) of sodium t-butoxide were mixed in 50 ml of toluene
and stirred at 75°C for 2 h. The reaction mixture was added to
ice/sodium chloride and extracted with ethyl acetate, the organic
phase was dried over sodium sulfate, and the solvent was removed
in a rotary evaporator. The product crystallized out and was
filtered off with suction and washed with pentane. 5.5 g (81~) of
the Boc-protected piperazine (melting point 111°C) were obtained.
5.2 g (16.6 mmol) of this substance were taken up in 17 ml of
dichloromethane and, at 0°C, 17 ml (0.22 mol) of trifluoroacetic
acid were slowly added. The mixture was stirred at 0°C for 4 h,
poured into ice-water and extracted with dichloromethane. The
aqueous phase was filtered, made alkaline and extracted with
dichloromethane. Drying over sodium sulfate and substantial
removal of the solvent were followed by dilution with diethyl
ether and precipitation of the hydrochloride with ethereal
hydrochloric acid. 3.2~g (67~) of the product were
obtained.(Melting point 293°C).
The following compounds were prepared by processes similar to the
two described: 1-(1-naphthyl)azepan (85°C, hydrochloride),
1-(1_naphthylmethyl)piperazine (oil), 4-(1-piperazinyl)indan
(oil), 1-(1-naphthyl)piperazine (82°C),
4-chloro-1-(1-piperazinyl)phthalazine (205°C, decomposition) and
4-(1-piperazinyl)quinazoline (320°C, hydrochloride). Other
derivatives were commercially available.
Preparation of the final product
2.9 g (10 mmol) of chloroethylpiperazine [b)] and 2.8 g (20 mmol)
of potassium carbonate were added to a solution of 2.4 g
(10 mmol) of tetrahydropyridopyrimidine [a)] in 40 ml of DMF.
After reaction at 90°C for 2 hours, the mixture was poured onto
ice-water and extracted with ethyl acetate. The organic phase was
washed with saturated brine and dried over sodium sulfate, and
the solvent was removed under reduced pressure. The remaining oil
was taken up in acetone, and the hydrochloride was precipitated
with isopropanol/HC1. 4 g (75~) of the product were obtained
(melting point 205°C).
0050/48479 ca o23o525s 2000-04-0~
13
NMR: CDC13 b 8.0 (s, 1H), 7.4 - 7.2.(m, 5H), 7.1 - 6.8 (m, 4H),
4.0 (t, 2H), 3.8 (s, 3H), 3.7 (s, 2H), 3.5 (s, 2H), 3.1 (br. s,
4H), 2.8 - 2.6 (m, lOH) ppm.
The following compounds were obtained in a similar way:
Example 2:
3-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-3,5,7,8-tetra-
hydro-4-oxo-6-benzylpyrido[3,4-d]pyrimidine (melting point 181°C,
hydrochloride).
Example 3:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3,5,7,8-tetra-
hydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine (melting point 198°C,
hydrochloride).
Example 4:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3,5,7,8-tetra-
hydro-4-oxo-6-benzylpyrido[3,4-d]pyrimidine (melting point 190°C,
hydrochloride).
Example 5:
3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropyl]-3,5,7,
8-tetrahydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine.
Example 6:
1.1-dimethyl [sic] 3-[2-[4-(1-naphthyl)-1-piperazinyl]ethyl]-
3,5,7,8-tetrahydro-4-oxo-pyrido[4,3-d]pyrimidine-6-carboxylate
(melting point 170°C, hydrochloride).
Example 7:
3-[2-[4-(4-isoquinolinyl)-1-piperazinyl]ethyl]-3,5,7,8-tetra-
hydro-4-oxo-6-benzylpyrido[4,3-d]pyrimidine (melting point 268°C,
hydrochloride).
Example 8:
0050/48479 CA 02305258 2000-04-07
10
14
3-[2-(4-(1-naphthyl)-1-piperazinyl]ethyl]-3,5,6,7,8-pentahydro-4-
oxopyrido[4,3-d]pyrimidine (melting point 272°C, hydrochloride).
Example 9:
3-[2-[4-(4-quinazolinyl)-1-piperazinyl]ethyl]-3,5,7,8-tetrahydro-
4-oxo-6-benzylpyrido[4,3-d]pyrimidine (melting point 258°C,
hydrochloride).
Example 10:
3-[2-[4-(1-naphthyl)-1-piperazinyl]ethyl]-3,5,7,8-tetrahydro-4-
oxo-6-benzylpyrido[4,3-d]pyrimidine (melting point 227°C,
hydrochloride).
Example 11:
3 [2-[4-(1-naphthyl)-1,2,3,6-tetrahydro-1-pyridinyl]eth-1-yl]-
3,5,7,8-tetrahydro-4-oxo-6-benzyl-pyrido[4,3-d]pyrimidine
(melting point 216°C, hydrochloride).
Synthesis of the starting materials
a) N-Boc-4-(trifluoromethanesulfonyloxy)tetrahydro-1,2,3,6-pyri-
dine
A solution of 13.2 g (0.13 mol) of diisopropylamine in 200 ml
of THF was deprotonated at -78°C with 100 mol of nBuLi (1.6M
in hexane) and, after 30 minutes at this temperature, 20.0 g~
(0.1 mol) of N-Boc-piperidone dissolved in 50 ml of THF were
added dropwise. After a further 3 hours at -78°C, a solution
of 39.3 g (0.11 mol) of N,N,-bistrifluoromethanesulfonyl-
aniline in 50 ml of THF were added, and the mixture was
allowed to reach room temperature overnight. For workup,
water was added, the mixture was extracted with ether, the
organic phases were washed with NaHC03 solution and water and
dried over sodium sulfate, and the solvent was evaporated
off. The crude product was purified by flash chromatography
(silica gel, mobile phase heptane/ethyl acetate = 3/1).
Yield: 20.2 g (60~ of theory)
0050/48479 ca o23os2ss 2000-04-0~
1H-NMR:(270 MHz,CDCl3)8= 1.4 (s, 9H); 2.4(m, 2H); 3.6 (t, 2H);
4.1 (m, 2H); 5.8 (m, 1H)ppm
5
b) N-Boc-4-(1-naphthyl)tetrahydro-1,2,3,6-pyridine
22 ml of 2M sodium carbonate solution, 7.63 g (44.4 mmol) of
naphthyl-1-boronic acid, 4.13 g (97.6 mmol) of lithium
chloride, 0.85 g (4.44 mmol) of copper(I) iodide and 2.1 g
10 (1'77 mmol) of tetrakistriphenylpalladium [sic] were
successively added to 14.7 g (44.4 mmol) of the compound
described above, dissolved in 115 ml of dimethoxyethane, and
the mixture was boiled for 4 h. For workup, aqueous ammonia
solution was added, extractive workup was carried out with
15 water and ethyl acetate and, after drying over sodium sulfate
and evaporation of the solvent, the residue was purified by
flash chromatography (silica gel, mobile phase heptane/ethyl
acetate = 4/1).
Yield: 8.2 g (57~ of theory)
1H-NMR (270 MHz, CDC13): b= 1.4 (s, 9H); 2.5 (m, 2H); 3.7(t,
2H); 4.1 (m, 2H); 5.8 (m, 1H); 7.2-7.5(m, 3H); 7.3-8.0 (m,
3H) ppm.
c) 4-(1-naphthyl)tetrahydro-1,2,3,6-pyridine
7.84 g (25.3 mmol) of N-Boc-4-(1-naphthyl)tetrahydro-1,2,3,6-
Pyridine were stirred with 200 ml of ethereal hydrochloric
acid at room temperature overnight, and the precipitated
product was filtered off and dried.
Yield: 5.5 g (88~ of theory).
d) Preparation of the final compound
0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-
oxo-6-benzylpyrido[4,3-d]pyrimidine and 2 ml (17 mmol) of
triethylamine were added to 0.51 g (2 mmol) of 4-(1-
naphthyl)tetrahydro-1,2,3,6-pyridine dissolved in 30 ml of
dry DMF, and the mixture was stirred at 120°C for 5 h. The
organic phase was diluted with ether, washed with water and
dried over sodium sulfate, and the solvent was removed under
reduced pressure. The resulting crude product was purified by
0050/48479 CA o23os2ss 2000-04-0~
16
chromatography to afford, after. precipitation of the salt
with ethereal hydrochloric acid solution, a white solid.
Yield: 0.2 g (20~ of theory)
Melting point: 237°C.
15
Example 12
3-[2-[4-(1-naphthyl)-1-piperidinyl]eth-1-yl]-3,5,7,8-tetrahydro-4
- oxo-6-benzylpyrido[4,3-d]pyrimidine
4-(1-naphthyl)piperidine
3.7 g (15.3 mmol) of 4-(1-naphthyl)tetrahydro-1,2,3,6-pyridine
were dissolved in methanol and, after addition of 0.8 g of
palladium on carbon, hydrogenated with hydrogen at room
temperature for 48 h. The catalyst was filtered off, and the
solvent was evaporated off.
Yield: 1.8 g (56~ of theory)
1H-NMR (270 MHz, CDC13)8 = 1.6-1.8 (m, 2H); 2.0 (m, 2H); 2.9 (dt,
2H); 3.3 (d, 2H); 3.5 (tt, 1H); 7.4-7.6 (m, 4H); 7.7 (d, 1H); 7.9
(d, 1H); 8.1 (d, 1H) ppm.
Preparation of the final compound
0.61 g (2 mmol) of 3-(2-chloroeth-1-yl)-3,5,7,8-tetrahydro-4-
oxo-6-benzylpyrido[4,3-d]pyrimidine and 2 ml (17 mmol) of
triethylamine were added to 0.42 g (2 mmol) of 4-(1-
naphthyl)piperidine dissolved in 30 ml of dry DMF, and the
mixture was stirred at 120°C for 5 h.._.The organic phase was
diluted with ether, washed with water and dried over sodium
sulfate, and the solvent was removed under reduced pressure. The
resulting crude product was purified by chromatography to afford,
after precipitation of the salt with ethereal hydrochloric acid
solution, a white solid.
Yield: 0.24 g (27~ of theory)
0050/48479 ca o23o525s 2000-04-07
17
1H-NMR (270 MHz, CDC13)8 = 8.3 (s, 1H), 8.0 (d,lH), 7.8 (d, 1H),
7.7 (t, 1H), 7.5 - 7.2 (m, 9H), 4.5 (s, 2H), 4.0 (s, 2H), 3.7 -
2.3 (m, 15H), 2.1 (d, 2H) ppm.
Further preferred novel compounds of the formula I are listed in
the following table.
15
25
35
45
0050/48479
CA 02305258 2000-04-07
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